Abstract
Specific peripheral sensory neurons respond to increases in extracellular osmolality but the mechanism responsible for excitation is unknown. Here we show that small increases in osmolality excite isolated mouse dorsal root ganglion (DRG) and trigeminal ganglion (TG) neurons expressing the cold-sensitive TRPM8 channel (transient receptor potential channel, subfamily M, member 8). Hyperosmotic responses were abolished by TRPM8 antagonists, and were absent in DRG and TG neurons isolated from Trpm8−/− mice. Heterologously expressed TRPM8 was activated by increased osmolality around physiological levels and inhibited by reduced osmolality. Electrophysiological studies in a mouse corneal preparation demonstrated that osmolality regulated the electrical activity of TRPM8-expressing corneal afferent neurons. Finally, the frequency of eye blinks was reduced in Trpm8−/− compared with wild-type mice and topical administration of a TRPM8 antagonist reduced blinking in wild-type mice. Our findings identify TRPM8 as a peripheral osmosensor responsible for the regulation of normal eye-blinking in mice.
Highlights
Specific peripheral sensory neurons respond to increases in extracellular osmolality but the mechanism responsible for excitation is unknown
We used [Ca2 þ ]i-measurements to identify osmosensitive populations of neurons isolated from mouse dorsal root ganglion (DRG) and trigeminal ganglion (TG)
To determine whether TRPM8 played an essential role in the hyperosmotic responses or acted as a marker for the responsive neurons, we examined the effects of TRPM8 antagonists and deletion of functional TRPM8 channels on the sensory neuron responses
Summary
Specific peripheral sensory neurons respond to increases in extracellular osmolality but the mechanism responsible for excitation is unknown. Individual neurons display sensitivities to one or more modalities and together they are responsible for sensing various thermal, chemical and mechanical stimuli Among these stimuli, an increase or decrease in extracellular osmolality can excite mammalian sensory neurons innervating various organs and tissues including the airways, gastrointestinal tract, liver and cornea[1,2,3,4,5,6]. Hyperosmotic solutions increase and hypo-osmotic solution decrease nerve terminal impulse (NTI) activity and osmotic activation of TRPM8 provides a peripheral neuronal drive that maintains normal eye blinking. These results demonstrate that TRPM8 acts as a multimodal sensor of thermal and osmotic stimuli and identify a new role for TRPM8 in the eye
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